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Yukio Shigeta - One of the best experts on this subject based on the ideXlab platform.
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long term clinical effects of Epalrestat an aldose reductase inhibitor on progression of diabetic neuropathy and other microvascular complications multivariate epidemiological analysis based on patient background factors and severity of diabetic neur
Diabetic Medicine, 2012Co-Authors: Nigishi Hotta, Ryuzo Kawamori, M Fukuda, Yukio ShigetaAbstract:Aims The goal of the study was to evaluate the efficacy of Epalrestat, an aldose reductase inhibitor, on diabetic retinopathy and diabetic nephropathy, based on analysis of the results of the Aldose Reductase Inhibitor–Diabetes Complications Trial, a 3-year multicentre comparative clinical trial of conventional therapy (control group) and Epalrestat therapy (Epalrestat group) in Japanese patients with mild diabetic neuropathy.
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stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long term treatment with an aldose reductase inhibitor Epalrestat
Diabetic Medicine, 2008Co-Authors: N Hotta, Jiro Nakamura, Ryuzo Kawamori, Yoshihito Atsumi, M Baba, H Kishikawa, Shinichi Oikawa, Nobuhiro Yamada, Hitoshi Yasuda, Yukio ShigetaAbstract:Aims The long-term efficacy of Epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to Epalrestat treatment. Methods Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor—Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity ≥ 40 m/s and with glycated haemoglobin (HbA1c) ≤ 9.0%. Longitudinal data on HbA1c and subjective symptoms of the patients for 3 years were analysed (Epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. Results Stratified subgroup analyses revealed significantly better efficacy of Epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the Epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of Epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA1c ≤ 7.0%). Conclusion Our results suggest that Epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.
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original article complications stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long term treatment with an aldose reductase inhibitor Epalrestat
2008Co-Authors: N Hotta, Ryuzo Kawamori, Yoshihito Atsumi, M Baba, H Kishikawa, Shinichi Oikawa, Nobuhiro Yamada, Hitoshi Yasuda, J Nakamura, Yukio ShigetaAbstract:Aims The long-term efficacy of Epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to Epalrestat treatment. Methods Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor—Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity ≥ 40 m/s and with glycated haemoglobin (HbA 1c ) ≤ 9.0%. Longitudinal data on HbA 1c and subjective symptoms of the patients for 3 years were analysed (Epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. Results Stratified subgroup analyses revealed significantly better efficacy of Epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the Epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of Epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA 1c ≤ 7.0%). Conclusion Our results suggest that Epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.
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a long term effect of Epalrestat on motor conduction velocity of diabetic patients ari diabetes complications trial adct
Diabetes Research and Clinical Practice, 2007Co-Authors: Kempei Matsuoka, Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Yoshitomo Oka, Motoaki Shichiri, Takayoshi Toyota, Nobuo Sakamoto, Yukio ShigetaAbstract:In order to study a long-term effect along with adverse action of Epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to Epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.
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clinical investigation of Epalrestat an aldose reductase inhibitor on diabetic neuropathy in japan multicenter study
Journal of Diabetes and Its Complications, 1996Co-Authors: Nigishi Hotta, Nobuo Sakamoto, Yukio Shigeta, Ryuichi Kikkawa, Yoshio GotoAbstract:A number of diabetic patients with diabetic neuropathy were treated with Epalrestat, an aldose reductase inhibitor, since this drug was launched into the market in Japan. More than 5000 patients with diabetic neuropathy who were treated with Epalrestat for 3-12 months were treated to analyze the efficacy and the adverse reactions of the drug in this study. The improvement rates of subjective symptoms (i.e., spontaneous pain, numbness, coldness, and hypoesthesia) was 75% (slightly improved or better) and those of nerve function tests (i.e., motor nerve conduction velocity, sensory nerve-conduction velocity, and vibration threshold) 36%. Adverse drug reactions were encountered in 129 cases (2.5%) out of 5249 patients, none of which were severe ones. Although data are limited, they strongly suggest that Epalrestat is a highly effective and safe agent for the treatment of diabetic neuropathy.
Nigishi Hotta - One of the best experts on this subject based on the ideXlab platform.
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Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial
2015Co-Authors: Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Kempei Matsuoka, Motoaki Shichiri, Mitsuyoshi Nakashima, Isao YoshimuraAbstract:OBJECTIVE — We sought to evaluate the long-term efficacy and safety of Epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN ANDMETHODS — Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) 40 m/s, and HbA1c 9 % were enrolled in this open-label, multicenter study and randomized to 150 mg/day Epalrestat or a control group. After excluding the withdrawals, 289 (Epalrestat group) and 305 (control group) patients were in-cluded in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception thresh-old [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS — Over the 3-year period, Epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P 0.001). Although a benefit with Epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, an
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long term clinical effects of Epalrestat an aldose reductase inhibitor on progression of diabetic neuropathy and other microvascular complications multivariate epidemiological analysis based on patient background factors and severity of diabetic neur
Diabetic Medicine, 2012Co-Authors: Nigishi Hotta, Ryuzo Kawamori, M Fukuda, Yukio ShigetaAbstract:Aims The goal of the study was to evaluate the efficacy of Epalrestat, an aldose reductase inhibitor, on diabetic retinopathy and diabetic nephropathy, based on analysis of the results of the Aldose Reductase Inhibitor–Diabetes Complications Trial, a 3-year multicentre comparative clinical trial of conventional therapy (control group) and Epalrestat therapy (Epalrestat group) in Japanese patients with mild diabetic neuropathy.
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a long term effect of Epalrestat on motor conduction velocity of diabetic patients ari diabetes complications trial adct
Diabetes Research and Clinical Practice, 2007Co-Authors: Kempei Matsuoka, Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Yoshitomo Oka, Motoaki Shichiri, Takayoshi Toyota, Nobuo Sakamoto, Yukio ShigetaAbstract:In order to study a long-term effect along with adverse action of Epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to Epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.
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long term clinical effects of Epalrestat an aldose reductase inhibitor on diabetic peripheral neuropathy the 3 year multicenter comparative aldose reductase inhibitor diabetes complications trial
Diabetes Care, 2006Co-Authors: Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Kempei Matsuoka, Yoshitomo Oka, Motoaki Shichiri, Takayoshi Toyota, Mitsuyoshi Nakashima, Isao Yoshimura, Nobuo SakamotoAbstract:OBJECTIVE —We sought to evaluate the long-term efficacy and safety of Epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS —Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) ≥40 m/s, and HbA1c ≤9% were enrolled in this open-label, multicenter study and randomized to 150 mg/day Epalrestat or a control group. After excluding the withdrawals, 289 (Epalrestat group) and 305 (control group) patients were included in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception threshold [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS —Over the 3-year period, Epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s ( P < 0.001). Although a benefit with Epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, and cramping improved significantly with Epalrestat versus the control group. The effects of Epalrestat on median MNCV were most evident in subjects with better glycemic control and with no or mild microangiopathies. CONCLUSIONS —Long-term treatment with Epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited microangiopathy.
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Polyol pathway and protein kinase C activity of rat Schwannoma cells.
Diabetes Metabolism Research and Reviews, 2003Co-Authors: Hideki Kamiya, Yoji Hamada, Jiro Nakamura, Eitaro Nakashima, Keiko Naruse, Koichi Kato, Yutaka Yasuda, Nigishi HottaAbstract:Background Polyol pathway hyperactivity-induced decreases in protein kinase C (PKC) activities have been proposed as a pathogenic mechanism of diabetic neuropathy. Increased PKC activities have recently been invoked in the pathogenesis of other diabetic complications, especially retinopathy, nephropathy, and macroangiopathy. However, it remains unclear whether PKC activities in neural cells such as Schwann cells are increased, decreased, or unchanged. This study investigated the effects of high glucose and increased polyol pathway activity on neural cell growth and PKC activities. Methods Rat Schwannoma cells were cultured in 5.5 or 20 mM glucose in the presence or absence of an aldose reductase inhibitor, Epalrestat (1 µM) for 14 days. Proliferation activities, PKC activities, and the protein expression of PKC isoforms were measured. Results Proliferation and PKC activities under the 20 mM glucose condition were significantly decreased compared to those under the 5.5 mM glucose condition and were prevented by Epalrestat. Among PKC isoforms, the protein expression of PKC-α under the 20 mM glucose condition was significantly reduced compared to that under the 5.5 mM glucose condition. Epalrestat significantly inhibited the decreased expression of PKC-α protein. There were no significant changes in the protein expression of PKC-β. Conclusions These results suggest that PKC, especially PKC-α activity, is decreased in Schwann cells exposed to high glucose and that this deficit is mediated through polyol pathway hyperactivity. Copyright © 2002 John Wiley & Sons, Ltd.
Ryuzo Kawamori - One of the best experts on this subject based on the ideXlab platform.
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Long-Term Clinical Effects of Epalrestat, an Aldose Reductase Inhibitor, on Diabetic Peripheral Neuropathy The 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial
2015Co-Authors: Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Kempei Matsuoka, Motoaki Shichiri, Mitsuyoshi Nakashima, Isao YoshimuraAbstract:OBJECTIVE — We sought to evaluate the long-term efficacy and safety of Epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. RESEARCH DESIGN ANDMETHODS — Subjects with diabetic neuropathy, median motor nerve conduction velocity (MNCV) 40 m/s, and HbA1c 9 % were enrolled in this open-label, multicenter study and randomized to 150 mg/day Epalrestat or a control group. After excluding the withdrawals, 289 (Epalrestat group) and 305 (control group) patients were in-cluded in the analyses. The primary end point was change from baseline in median MNCV at 3 years. Secondary end points included assessment of other somatic nerve function parameters (minimum F-wave latency [MFWL] of the median motor nerve and vibration perception thresh-old [VPT]), cardiovascular autonomic nerve function, and subjective symptoms. RESULTS — Over the 3-year period, Epalrestat prevented the deterioration of median MNCV, MFWL, and VPT seen in the control group. The between-group difference in change from baseline in median MNCV was 1.6 m/s (P 0.001). Although a benefit with Epalrestat was observed in cardiovascular autonomic nerve function variables, this did not reach statistical significance compared with the control group. Numbness of limbs, sensory abnormality, an
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long term clinical effects of Epalrestat an aldose reductase inhibitor on progression of diabetic neuropathy and other microvascular complications multivariate epidemiological analysis based on patient background factors and severity of diabetic neur
Diabetic Medicine, 2012Co-Authors: Nigishi Hotta, Ryuzo Kawamori, M Fukuda, Yukio ShigetaAbstract:Aims The goal of the study was to evaluate the efficacy of Epalrestat, an aldose reductase inhibitor, on diabetic retinopathy and diabetic nephropathy, based on analysis of the results of the Aldose Reductase Inhibitor–Diabetes Complications Trial, a 3-year multicentre comparative clinical trial of conventional therapy (control group) and Epalrestat therapy (Epalrestat group) in Japanese patients with mild diabetic neuropathy.
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stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long term treatment with an aldose reductase inhibitor Epalrestat
Diabetic Medicine, 2008Co-Authors: N Hotta, Jiro Nakamura, Ryuzo Kawamori, Yoshihito Atsumi, M Baba, H Kishikawa, Shinichi Oikawa, Nobuhiro Yamada, Hitoshi Yasuda, Yukio ShigetaAbstract:Aims The long-term efficacy of Epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to Epalrestat treatment. Methods Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor—Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity ≥ 40 m/s and with glycated haemoglobin (HbA1c) ≤ 9.0%. Longitudinal data on HbA1c and subjective symptoms of the patients for 3 years were analysed (Epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. Results Stratified subgroup analyses revealed significantly better efficacy of Epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the Epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of Epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA1c ≤ 7.0%). Conclusion Our results suggest that Epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.
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original article complications stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long term treatment with an aldose reductase inhibitor Epalrestat
2008Co-Authors: N Hotta, Ryuzo Kawamori, Yoshihito Atsumi, M Baba, H Kishikawa, Shinichi Oikawa, Nobuhiro Yamada, Hitoshi Yasuda, J Nakamura, Yukio ShigetaAbstract:Aims The long-term efficacy of Epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to Epalrestat treatment. Methods Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor—Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity ≥ 40 m/s and with glycated haemoglobin (HbA 1c ) ≤ 9.0%. Longitudinal data on HbA 1c and subjective symptoms of the patients for 3 years were analysed (Epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. Results Stratified subgroup analyses revealed significantly better efficacy of Epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the Epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of Epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA 1c ≤ 7.0%). Conclusion Our results suggest that Epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.
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a long term effect of Epalrestat on motor conduction velocity of diabetic patients ari diabetes complications trial adct
Diabetes Research and Clinical Practice, 2007Co-Authors: Kempei Matsuoka, Nigishi Hotta, Yasuo Akanuma, Ryuzo Kawamori, Yoshitomo Oka, Motoaki Shichiri, Takayoshi Toyota, Nobuo Sakamoto, Yukio ShigetaAbstract:In order to study a long-term effect along with adverse action of Epalrestat, an aldose reductase inhibitor, a randomized, prospective study was conducted over the period of 3 years at 112 facilities. Six hundred and three diabetic patients with median motor conduction velocity (MCV)>40 m/s, HbA1c<9% were randomly allocated to Epalrestat (50 mg/day p.o. ac, t.i.d.) group (E group: n=289, age: 61+/-9.8 y.o.) and a control group (C group: n=305, age: 61+/-9.1 y.o.). MCV was measured once a year for 3 years. MCV (m/s, M+/-S.D.) on baseline, 1 year and 3 years, was 52.0+/-4.5, 52.2+/-4.9, 52.1+/-4.6 in E group and 53.3+/-4.4, 52.4+/-4.2, 52.0+/-4.6 in C group, respectively. After 3 years, difference from the baseline was significant (p<0.0001, E versus C). Among the subjects with HbA1c<7.0%, C group showed marked deterioration of MCV while in E group, there was no significant deterioration (p<0.001). Although, the subjects with pre-proliferative or proliferative retinopathy, there was no difference between E and C groups for 3 years, in subjects with background retinopathy or without retinopathy, deterioration rate of E group was significantly less than that of C group (p<0.0001). Epalrestat was found to prevent deterioration of MCV especially in well-controlled patients without advanced complications. No remarkable side effects serious enough to discontinue the study was observed.
Jiro Nakamura - One of the best experts on this subject based on the ideXlab platform.
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stratified analyses for selecting appropriate target patients with diabetic peripheral neuropathy for long term treatment with an aldose reductase inhibitor Epalrestat
Diabetic Medicine, 2008Co-Authors: N Hotta, Jiro Nakamura, Ryuzo Kawamori, Yoshihito Atsumi, M Baba, H Kishikawa, Shinichi Oikawa, Nobuhiro Yamada, Hitoshi Yasuda, Yukio ShigetaAbstract:Aims The long-term efficacy of Epalrestat, an aldose reductase inhibitor, in improving subjective symptoms and nerve function was comprehensively assessed to identify patients with diabetic peripheral neuropathy who responded to Epalrestat treatment. Methods Stratified analyses were conducted on data from patients in the Aldose Reductase Inhibitor—Diabetes Complications Trial (ADCT). The ADCT included patients with diabetic peripheral neuropathy, median motor nerve conduction velocity ≥ 40 m/s and with glycated haemoglobin (HbA1c) ≤ 9.0%. Longitudinal data on HbA1c and subjective symptoms of the patients for 3 years were analysed (Epalrestat n = 231, control subjects n = 273). Stratified analyses based on background variables (glycaemic control, grades of retinopathy or proteinuria) were performed to examine the relationship between subjective symptoms and nerve function. Multiple logistic regression analyses were conducted. Results Stratified subgroup analyses revealed significantly better efficacy of Epalrestat in patients with good glycaemic control and less severe diabetic complications. In the control group, no improvement in nerve function was seen regardless of whether symptomatic benefit was obtained. In the Epalrestat group, nerve function deteriorated less or improved in patients whose symptoms improved. The odds ratio of the efficacy of Epalrestat vs. control subjects was approximately 2 : 1 (4 : 1 in patients with HbA1c ≤ 7.0%). Conclusion Our results suggest that Epalrestat, an aldose reductase inhibitor, will provide a clinically significant means of preventing and treating diabetic neuropathy if used in appropriate patients.
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Polyol pathway and protein kinase C activity of rat Schwannoma cells.
Diabetes Metabolism Research and Reviews, 2003Co-Authors: Hideki Kamiya, Yoji Hamada, Jiro Nakamura, Eitaro Nakashima, Keiko Naruse, Koichi Kato, Yutaka Yasuda, Nigishi HottaAbstract:Background Polyol pathway hyperactivity-induced decreases in protein kinase C (PKC) activities have been proposed as a pathogenic mechanism of diabetic neuropathy. Increased PKC activities have recently been invoked in the pathogenesis of other diabetic complications, especially retinopathy, nephropathy, and macroangiopathy. However, it remains unclear whether PKC activities in neural cells such as Schwann cells are increased, decreased, or unchanged. This study investigated the effects of high glucose and increased polyol pathway activity on neural cell growth and PKC activities. Methods Rat Schwannoma cells were cultured in 5.5 or 20 mM glucose in the presence or absence of an aldose reductase inhibitor, Epalrestat (1 µM) for 14 days. Proliferation activities, PKC activities, and the protein expression of PKC isoforms were measured. Results Proliferation and PKC activities under the 20 mM glucose condition were significantly decreased compared to those under the 5.5 mM glucose condition and were prevented by Epalrestat. Among PKC isoforms, the protein expression of PKC-α under the 20 mM glucose condition was significantly reduced compared to that under the 5.5 mM glucose condition. Epalrestat significantly inhibited the decreased expression of PKC-α protein. There were no significant changes in the protein expression of PKC-β. Conclusions These results suggest that PKC, especially PKC-α activity, is decreased in Schwann cells exposed to high glucose and that this deficit is mediated through polyol pathway hyperactivity. Copyright © 2002 John Wiley & Sons, Ltd.
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aldose reductase inhibition ameliorates pupillary light reflex and f wave latency in patients with mild diabetic neuropathy
Diabetes Care, 2001Co-Authors: Mikihiro Nakayama, Yoji Hamada, Hideki Kamiya, Jiro Nakamura, Yutaka Yasuda, Sadao Chaya, Ryuichi Mizubayashi, Naoki Koh, Nigishi HottaAbstract:OBJECTIVE —The present study was conducted to investigate the effect of an aldose reductase inhibitor, Epalrestat, on autonomic and somatic neuropathy at an early stage in type 2 diabetic patients by assessing the pupillary light reflex and minimum latency of the F-wave. RESEARCH DESIGN AND METHODS —A total of 30 diabetic patients with subclinical or mild diabetic neuropathy were randomly allocated to a control group ( n = 15) and Epalrestat (150 mg/day) group ( n = 15). After 24 weeks, the pupillary light reflex test, cardiovascular autonomic function tests, and nerve conduction study were performed. RESULTS —The beneficial effect of Epalrestat on the pupillary light reflex was observed in the minimum diameter after light stimuli ( P = 0.044), constriction ratio ( P = 0.014), and maximum velocity of constriction ( P = 0.008). Among cardiovascular autonomic nerve functions, the ratio of the longest expiratory R-R interval to the shortest inspiratory R-R interval during deep breathing was significantly improved by Epalrestat ( P = 0.037). Minimum latencies of F-wave of median and tibial motor nerves were significantly shortened by Epalrestat ( P = 0.002 and P = 0.001, respectively); however, no significant effects were observed in motor or sensory nerve conduction velocity. CONCLUSIONS —These observations suggest that Epalrestat may have therapeutic value at the early stage of diabetic neuropathy and that the pupillary light reflex and minimum latency of F-wave may be useful indicators of diabetic neuropathy.
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Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity.
Diabetologia, 2001Co-Authors: Jiro Nakamura, Yoji Hamada, Eitaro Nakashima, Koichi Kato, Yutaka Yasuda, Y Kasuya, Keiji Naruse, Nigishi HottaAbstract:Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose with or without an aldose reductase inhibitor, Epalrestat, or a PKC-β specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/l glucose showed statistically significant increases in protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although Epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of Epalrestat on proliferation activities and expression of the PDGF-β receptor were more prominent than those of LY333 531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-βII isoform was normalized by Epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-β receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication. [Diabetologia (2001) 44: 480–487]
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Epalrestat an aldose reductase ihibitor reduces the levels of nepsilon carboxymethyl lysine protein adducts and their precursors in erythrocytes from diabetic patients
Diabetes Care, 2000Co-Authors: Yoji Hamada, Jiro Nakamura, Keiko Naruse, Koichi Kato, Y Kasuya, T Komori, Ryuji Nagai, Seikoh Horiuchi, Nigishi HottaAbstract:OBJECTIVE: To clarify the role of the polyol pathway in the intracellular formation of advanced glycation end products in human tissues, we examined the effects of Epalrestat, an aldose reductase inhibitor, on the level of Nepsilon-(carboxymethyl)lysine (CML) along with 3-deoxyglucosone (3-DG) and triosephosphates in erythrocytes from diabetic patients. Plasma thiobarbituric acid-reactive substances (TBARS) were also determined as indicators of oxidative stress. RESEARCH DESIGN AND METHODS: Blood samples were collected from 12 nondiabetic volunteers, 38 untreated type 2 diabetic patients, and 16 type 2 diabetic patients who had been treated with 150 mg Epalrestat/day. Blood samples were also collected from 14 of the untreated type 2 diabetic patients before and after the administration of Epalrestat for 2 months. The amount of erythrocyte CML was determined by a competitive enzyme-linked immunosorbent assay, and 3-DG was measured by high-performance liquid chromatography RESULTS: In diabetic patients not treated with Epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 +/- 5.0 vs. 31.0 +/- 5.2 U/g protein, P < 0.05) and was significantly lower in patients receiving Epalrestat (33.1 +/- 3.8 U/g protein, P < 0.05). Similar results were observed with 3-DG. The treatment of patients with Epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 +/- 5.6 at baseline vs. 34.4 +/- 5.0 U/g protein, P < 0.01) along with erythrocyte 3-DG (P < 0.05), triosephosphates (P < 0.05), fructose (P < 0.05), sorbitol (P < 0.05), and plasma TBARS (P < 0.05) without changes in plasma glucose and HbA(1c) levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P < 0.01) or fructose (r = 0.40, P < 0.05) levels in diabetic patients. CONCLUSIONS: The results indicate that Epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.
Karen L Goa - One of the best experts on this subject based on the ideXlab platform.
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Epalrestat a review of its pharmacology and therapeutic potential in late onset complications of diabetes mellitus
Drugs & Aging, 1993Co-Authors: John W Steele, Diana Faulds, Karen L GoaAbstract:Epalrestat is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycaemic conditions Epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity, and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting were also improved. Similar benefits were seen in a comparison with historical controls. Epalrestat 300 mg/day for 1 or 3 years was also significantly superior to placebo or no treatment in improving electroretinogram parameters and photo stress recovery time in patients with diabetic retinopathy. Improvements were also documented by funduscopy and fluorescein angiography. Epalrestat appeared most effective in patients with less severe diabetes mellitus and more recent development of late-onset complications. Epalrestat is apparently well tolerated with predominantly minor adverse events reported in clinical trials. Liver enzyme elevations were most commonly reported but generally resolved spontaneously on dose reduction or discontinuation. The effects of age and renal impairment on the efficacy and tolerability of Epalrestat require clarification, and data on its use in other late-onset complications of diabetes such as nephropathy are also lacking. Comparisons with other aldose reductase inhibitors are also required to fully determine the role of Epalrestat. The suggested ability of Epalrestat to prevent the onset of diabetic complications should also be investigated. Thus, available data suggest Epalrestat produces some improvement in the late-onset neuropathy and retinopathy associated with diabetes mellitus, although additional trials are required to determine whether ongoing therapy is necessary to maintain the improvements achieved and to confirm tolerability in the long term. Nevertheless, preliminary results suggest that Epalrestat may be a useful drug in an area where there is a need for effective therapy.
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Epalrestat
Drugs & Aging, 1993Co-Authors: John W Steele, Diana Faulds, Karen L GoaAbstract:Synopsis Epalrestat is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycaemic conditions Epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity, and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting were also improved. Similar benefits were seen in a comparison with historical controls. Epalrestat 300 mg/day for 1 or 3 years was also significantly superior to placebo or no treatment in improving electroretinogram parameters and photo stress recovery time in patients with diabetic retinopathy. Improvements were also documented by funduscopy and fluorescein angiography. Epalrestat appeared most effective in patients with less severe diabetes mellitus and more recent development of late-onset complications. Epalrestat is apparently well tolerated with predominantly minor adverse events reported in clinical trials. Liver enzyme elevations were most commonly reported but generally resolved spontaneously on dose reduction or discontinuation. The effects of age and renal impairment on the efficacy and tolerability of Epalrestat require clarification, and data on its use in other late-onset complications of diabetes such as nephropathy are also lacking. Comparisons with other aldose reductase inhibitors are also required to fully determine the role of Epalrestat. The suggested ability of Epalrestat to prevent the onset of diabetic complications should also be investigated. Thus, available data suggest Epalrestat produces some improvement in the late-onset neuropathy and retinopathy associated with diabetes mellitus, although additional trials are required to determine whether ongoing therapy is necessary to maintain the improvements achieved and to confirm tolerability in the long term. Nevertheless, preliminary results suggest that Epalrestat may be a useful drug in an area where there is a need for effective therapy. Pharmacology The sorbitol (polyol) metabolic pathway, an alternative glucose reduction pathway involving the enzymes aldose reductase and sorbitol dehydrogenase, is thought to be activated by hyperglycaemic conditions. Intracellular accumulation of sorbitol during hyperglycaemia is considered to be at least partially responsible for the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat, an uncompetitive aldose reductase inhibitor, significantly reduces intracellular sorbitol accumulation in sciatic nerve, erythrocytes and ocular tissues from animal models, and in erythrocytes in humans, with diabetes mellitus, without affecting glucose levels. Epalrestat also increased sodium-dependent myoinositol uptake into sciatic nerve tissue in rats and skin fibroblasts from patients with diabetes, and attenuated nerve conduction velocity and retinal changes commonly seen in patients with diabetic neuropathy and retinopathy, respectively. In healthy volunteers, distribution of Epalrestat is rapid and peak plasma concentrations are reached 1 to 2 hours after oral doses of 50 to 200mg. The elimination half-life is about 1 hour, and unchanged Epalrestat and sulphate conjugates of the mono- and dihydroxyphenyl metabolites are found in the urine. Therapeutic Potential Oral Epalrestat 150 mg/day for 12 weeks produced improvements in motor and sensory nerve conduction velocity, and vibration sensation perception compared with placebo, in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, orthostatic fainting, and constipation/diarrhoea also improved. A comparison with historical controls showed similar benefits, as did a comparison with methylcobalamine. These findings are supported by the results of noncomparative trials of 4 weeks’ to 1 years’ duration, including a total of 365 patients with diabetic neuropathy. Comparative studies of 1 or 3 years’ duration in patients with diabetic retinopathy show that Epalrestat 300 mg/day is significantly more effective than placebo or no treatment, in improving or preventing deterioration of ocular signs and symptoms. Epalrestat appears to be most effective in patients in whom diabetes mellitus is less severe and where late-onset complications are recent. Tolerability Epalrestat has been well tolerated in mainly noncomparative Japanese clinical trials of up to 3 years’ duration. Adverse events reported most frequently were minor liver enzyme elevations, diarrhoea, erythema, skin bullae and elevated serum creatinine levels. Epalrestat was as well tolerated as placebo and methylcobalamine in comparative trials. Dosage and Administration The recommended dosage of oral Epalrestat is 50mg 3 times daily before meals. Epalrestat is particularly recommended for use in patients with high glycosylated haemoglobin levels (indicating failure to control hyperglycaemia), despite standard pharmacological and nonpharmacological intervention. Alternative treatment should be considered if an adequate response to Epalrestat is not observed after 12 weeks of therapy.